Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia.
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PMID:Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks. 2308 84

Postnatal administration of phencyclidine (PCP) in rodents causes major brain dysfunction leading to severe disturbances in behavior lasting into adulthood. This model is routinely employed to model psychiatric disorders such as schizophrenia, as it reflects schizophrenia-related brain disturbances including increased apoptosis, and disruptions to myelin and plasticity processes. Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1) is a potent negative regulator of both axonal myelination and neurite extension. The Nogo receptor (NgR)/tumor necrosis factor (TNF) receptor orphan Y (TROY) and/or p75 neurotrophin receptor (p75) complex, with no lysine (K) (WNK1) and myelin transcription factor 1 (Myt1) are co-receptors or cofactors in Lingo-1 signaling pathways in the brain. We have examined the developmental trajectory of these proteins in a neurodevelopmental model of schizophrenia using PCP to determine if Lingo-1 pathways are altered in the prefrontal cortex throughout different stages of life. Sprague-Dawley rats were injected with PCP (10 mg/kg) or saline on postnatal days (PN)7, 9, and 11 and killed at PN12, 5 or 14 weeks for measurement of Lingo-1 signaling proteins in the prefrontal cortex. Myt1 was decreased by PCP at PN12 (P=0.045), and at 14 weeks PCP increased Lingo-1 (P=0.037), TROY (P=0.017), and WNK1 (P=0.003) expression. This is the first study reporting an alteration in Lingo-1 signaling proteins in the rat prefrontal cortex both directly after PCP treatment in early development and in adulthood. We propose that Lingo-1 pathways may be negatively regulating myelination and neurite outgrowth following the administration of PCP, and that this may have implications for the cortical dysfunction observed in schizophrenia.
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PMID:Perinatal administration of phencyclidine alters expression of Lingo-1 signaling pathway proteins in the prefrontal cortex of juvenile and adult rats. 3271 88